Abstract: On the occasion of its recent approval for relapsed follicular
lymphoma, we review the design and development of the pan-class I PI3K
inhibitor copanlisib as a drug for the treatment of B-cell malignancies in
comparison with other kinase inhibitors targeting B-cell-receptor signaling, in
particular with strictly isoform-δ-selective idelalisib. In agreement with previously
defined PI3K-inhibitor chemotypes, the 2,3-dihydroimidazo[1,2-c]quinazoline
scaffold of copanlisib adopts a flat conformation in the adenine-binding pocket
of the catalytic p110 subunit and further extends into a deeper-affinity pocket
in contrast to idelalisib, the quinazoline moiety of which is accommodated in a
newly created selectivity pocket. Copanlisib shows higher potency than other
clinically developed PI3K inhibitors against all four class I isoforms, with
approximately tenfold preference for p110α and p110δ. Owing to its potency and
isoform profile, copanlisib exhibits cell-type-specific cytotoxicity against
primary chronic lymphocytic leukemia cells and diffuse large B-cell lymphoma
(DLBCL) cell lines at nanomolar concentrations. Moreover, copanlisib differs
from idelalisib in regard to intravenous versus oral administration and weekly
versus twice-daily dosing. In regard to adverse effects, intermittent
intravenous treatment with copanlisib leads to fewer gastrointestinal
toxicities compared with continuous oral dosing of idelalisib. In relapsed
follicular lymphoma, copanlisib appears more effective and especially better
tolerated than other targeted therapies. Copanlisib extends existing treatment
options for this subtype of indolent non-Hodgkin lymphoma and also shows
promising response rates in DLBCL, especially of the activated B-cell type.Keywords: targeted
therapy, B-cell receptor signaling, p110 isoforms, non-Hodgkin lymphoma,
leukemia